Polymerizing proteins are important determinants of the morphological, rheological and osmotic properties of cells, in both pathological states (e.g., sickle cell disease) and normal physiology (e.g., cytoskeletal structure). The distinctive behavior of polymerizing proteins results from the formation of long rigid particles which align spontaneously due to packing constraints. Previous theories have treated the polymerization and alignment as independent processes. However, because the polymerization is reversible, the distributions of polymer lenghts and orientations are reciprocally coupled and evolve jointly. The results of our preliminary calculations show that this view provides a better explanation for calorimetric and osmotic pressure measurements on sickle cell homoglobin than previous descriptions. However, the simple form of the model employed in this initial work could not address other important issues relevant to biochemical systems. We therefore propose to develop more appropriate models which will enable use to examine the effects of polymer structure, nucleation limited polymer numbers, anisotropic interparticle interactions, protein heterogeneity and the binding of small regulatory molecules. The theoretical development will be guided by comparison of the predicted thermodynamics with that observed by osmotic pressure measurements on systematically varied solutions of sickle cell homeglobin and other polymerizing proteins. The results will be used to elucidate the osmotic behavior of erythrocytes in sickle cell disease as reflected in the distribution of cell densities observed under various conditions. By identifying the most critical determinants of the phase behavior of sickle cell hemoglobin, our analysis will provide an improved conceptual framework for the development of therapeutic strategies. These studies will also provide a better understanding of factors influencing the organization of cytoskeletal proteins into fibrillar structures.